Classifications

• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
  • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
  • C12P7/00—Preparation of oxygen-containing organic compounds
  • C12P7/62—Carboxylic acid esters
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
  • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
  • C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
  • C12P41/004—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of alcohol- or thiol groups in the enantiomers or the inverse reaction
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
  • C12P7/00—Preparation of oxygen-containing organic compounds
  • C12P7/02—Preparation of oxygen-containing organic compounds containing a hydroxy group
  • C12P7/04—Preparation of oxygen-containing organic compounds containing a hydroxy group acyclic

Definitions

• the present invention relates to a new process for the easy preparation of optically active alcohols and their esters by reacting the hydroxy group of racemic 1,2-diol derivatives represented by the general formula 1 stereospecifically after adding succinic anhydride as an acylating agent and lipases as biocatalysts to organic solvents.
• This invention relates to a process for preparing the products of high optical purity in high yield by separating alcohols from their esters easily after reaction using succinic anhydride as an acylating agent.
• Racemic alcohols represented by the general formula 1 in scheme 1 are composed of (S)-alcohols and (R)-alcohols respectively and they are used as intermediates in preparing important pharmaceuticals.
• the objective of this invention is to provide the method of preparing optically active alcohols and their esters of high optical purity in high yield by recovering the products easily after reaction using succinic anhydride as an acylating agent.
• this invention consists of the process for reacting racemic alcohol represented by the general formula 1 stereospecifically by lipase using succinic anhydride as an acylating agent in organic solvent.
• lipase commercially available ones and, if necessary, home-made ones can be used.
• Non-limiting examples of the commercially available lipase include Novozyme 435 from Novo Ltd. and those manufactured by Amano Inc. such as PS, PS-D, PS-C and AK lipase.
• optically active alcohols and their esters are separated by known methods such as solvent extraction, crystallization and so on.
• Optically active 2-hydroxy-3-azidopropyl t-butylate was determined by a gas chromatography(Donam Instruments Inc. Model DS 6200) equipped with chiral column(Chiraldex B-PM, Alltech). The oven temperature was maintained initially at
• Optically active 2-hydroxypropyl p-toluenesulfonate was determined by a HPLC(Lab Alliance Inc. Model 201) equipped with chiral column(Chiralcel OB-H, Daicel) using hexane and isopropyl alcohol mixture(80:20) as mobile phase.
• the Absorbance was 220nm and flow rate was 0.65ml /min.
• the typical retention time of the components in this invention was as follows:
• Optically active 2-hydroxypropyl tritylate was determined using chiral column(Chiralcel OJ-H,
• Example 1 t-butyl glycidyl ether(0.5g) was dissolved in the mixture of ethanol and distilled water.
• Example 2 l,2-Propanediol(7.6ml) was dissolved in dichloromethane(50ml) at room temperature, 4- dimethylaminopyridine(0.49g) and p-toluenesulfonyl chloride(24.7g) were added to it respectively and maintained at 0 ⁇ 5°C . And triethylamine(13.2ml) was added slowly for 1 hour under nitrogen atmosphere. Then the reaction was carried out for 24 hours at room temperature. After reaction, the reaction mixture was poured into an ice-water mixture and extracted with dichloromethane. The combined organic phase was dried over and 2-hydroxypropyl p-toluenesulfonate(17.3g, yield 73%) was obtained and confirmed by FT-NMR.
• Succinic anhydride(O.lg) and t-butylmethylether(5ml) were placed in a 15ml vial. Then, racemic 2-hydroxypropyl p-toluenesulfonate(0.05g) and PS lipase(0.2g) were added to the mixture. The reaction was carried out for 22 hours at 45°C and (S)-2-hydroxypropyl p-toluenesulfonate(99.0% ee) was obtained at 54.4% conversion.
• Example 3 Instead of 1,2-propanediol, 3-chloro-l,2-propanediol(l 1.05ml) was dissolved in dichloromethane (50ml), and the synthesis was performed as shown in Example 2.
• Triethylamine(3.29ml) was added slowly for 1 hour under nitrogen atmosphere. Then the synthesis was performed as shown in Example 2.
• Example 6 l,2-Propanediol(lg) was dissolved in dichloromethane(l ⁇ ml) at room temperature, 4- dimethylaminopyridine(0.044g) and triphenylmethyl chloride(2.78g) were added to it respectively and maintained at 0 ⁇ 5°C . Triethylamine( 1.89ml) was added slowly for 1 hour under nitrogen atmosphere. Then the synthesis was performed as shown in Example 2.
• the starting material can be synthesized at lower cost by simple method.
• succinic anhydride as an acylating agent, alcohols and their esters of high optical purity could be produced in high yield after enzymatic reaction. Therefore it is a very useful process on the industrial scale.

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• Preparation Of Compounds By Using Micro-Organisms (AREA)

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• 2003
  • 2003-06-03 KR KR10-2003-0035470A patent/KR100527231B1/ko not_active IP Right Cessation
• 2004
  • 2004-06-02 WO PCT/KR2004/001313 patent/WO2004106534A1/en active Application Filing
  • 2004-06-02 US US10/558,057 patent/US20060234362A1/en not_active Abandoned

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